Format

Send to

Choose Destination
J Immunol. 2014 Sep 1;193(5):2587-99. doi: 10.4049/jimmunol.1302344. Epub 2014 Jul 28.

Specific increase in potency via structure-based design of a TCR.

Author information

1
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Program in Structural Biology, New York University School of Medicine, New York, NY 10016;
2
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
3
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
4
Department of Chemistry, New York University, New York, NY 10012;
5
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
6
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
7
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Program in Structural Biology, New York University School of Medicine, New York, NY 10016; Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY 10016 Michelle.Krogsgaard@nyumc.org.

Abstract

Adoptive immunotherapy with Ag-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor Ags are nonreactive "self" proteins, which presents an immunotherapy design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, which persist after transfer in ∼30% of patients and effectively destroy tumor cells in vivo. Although encouraging, the limited clinical responses underscore the need for enrichment of T cells with desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLA-A2, which elicits full T cell activation to trigger immune responses. We analyzed the effects of selected TCR point mutations on T cell activation potency and analyzed cross-reactivity with related Ags. Our results showed that the mutated TCRs had improved T cell activation potency while retaining a high degree of specificity. Such affinity-optimized TCRs have demonstrated to be very specific for Mart-1 (27L), the epitope for which they were structurally designed. Although of somewhat limited clinical relevance, these studies open the possibility for future structural-based studies that could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity-derived effects.

PMID:
25070852
PMCID:
PMC4205480
DOI:
10.4049/jimmunol.1302344
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center